Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-helminth Immunity in the Small Intestine but Are Dispensable for Anti-protist Immunity.

Helminths, allergens, and certain protists induce type 2 immune responses, but the underlying mechanisms of immune activation remain poorly understood. In the small intestine, chemosensing by epithelial tuft cells results in the activation of group 2 innate lymphoid cells (ILC2s), which subsequently drive increased tuft cell frequency. This feedforward circuit is essential for intestinal remodeling and helminth clearance. ILC2 activation requires tuft-cell-derived interleukin-25 (IL-25), but whether additional signals regulate the circuit is unclear. Here, we show that tuft cells secrete cysteinyl leukotrienes (cysLTs) to rapidly activate type 2 immunity following chemosensing of helminth infection. CysLTs cooperate with IL-25 to activate ILC2s, and tuft-cell-specific ablation of leukotriene synthesis attenuates type 2 immunity and delays helminth clearance. Conversely, cysLTs are dispensable for the tuft cell response induced by intestinal protists. Our findings identify an additional tuft cell effector function and suggest context-specific regulation of tuft-ILC2 circuits within the small intestine.

CD44 acts as a coreceptor for cell-specific enhancement of signaling and regulatory T cell induction by TGM1, a parasite TGF-ß mimic.

Long-lived parasites evade host immunity through highly evolved molecular strategies. The murine intestinal helminth, Heligmosomoides polygyrus, down-modulates the host immune system through release of an immunosuppressive TGF-ß mimic, TGM1, which is a divergent member of the CCP (Sushi) protein family. TGM1 comprises 5 domains, of which domains 1-3 (D1/2/3) bind mammalian TGF-ß receptors, acting on T cells to induce Foxp3+ regulatory T cells; however, the roles of domains 4 and 5 (D4/5) remain unknown. We noted that truncated TGM1, lacking D4/5, showed reduced potency. Combination of D1/2/3 and D4/5 as separate proteins did not alter potency, suggesting that a physical linkage is required and that these domains do not deliver an independent signal. Coprecipitation from cells treated with biotinylated D4/5, followed by mass spectrometry, identified the cell surface protein CD44 as a coreceptor for TGM1. Both full-length and D4/5 bound strongly to a range of primary cells and cell lines, to a greater degree than D1/2/3 alone, although some cell lines did not respond to TGM1. Ectopic expression of CD44 in nonresponding cells conferred responsiveness, while genetic depletion of CD44 abolished enhancement by D4/5 and ablated the ability of full-length TGM1 to bind to cell surfaces. Moreover, CD44-deficient T cells showed attenuated induction of Foxp3 by full-length TGM1, to levels similar to those induced by D1/2/3. Hence, a parasite protein known to bind two host cytokine receptor subunits has evolved a third receptor specificity, which serves to raise the avidity and cell type-specific potency of TGF-ß signaling in mammalian cells.

Quantitative assessment of spicule length in Heligmosomoides spp. (Nematoda, Heligmosomidae): distinction between H. bakeri, H. polygyrus and H. glareoli.

Nematode spicules play a vital role in the reproductive activity of species that possess them. Our primary objective was to compare the lengths of spicules of the laboratory mouse (Mus musculus) ­ maintained isolate H. bakeri ­ with those of H. polygyrus from naturally infected wood mice (Apodemus sylvaticus). On a more limited scale, we also included H. glareoli from bank voles (Myodes glareolus), a species reputed to possess longer spicules than either of the 2 former species. In total, we measured 1264 spicules (H. bakeri, n = 614; H. polygyrus n = 582; and H. glareoli, n = 68). There was a highly significant difference between the spicule lengths of the Nottingham-maintained H. bakeri (mean = 0.518 mm) and H. polygyrus (0.598 mm) from 11 different localities across the British Isles. A comparison of the spicules of H. bakeri maintained in 4 different laboratories in 3 continents revealed a range in the mean values from 0.518 to 0.540 mm, while those of worms from Australian wild house mice were shorter (0.480 mm). Mean values for H. polygyrus from wood mice from the British Isles ranged from 0.564 to 0.635 mm, although isolates of this species from Norway had longer spicules (0.670 mm). In agreement with the literature, the spicules of H. glareoli were considerably longer (1.098 mm). Since spicules play a vital role in the reproduction of nematode species that possess them, the difference in spicule lengths between H. bakeri and H. polygyrus adds to the growing evidence that these 2 are quite distinct species and likely reproductively isolated.

Helminth parasites of the wood mouse Apodemus sylvaticus in Southern England: levels of infection, species richness and interactions between species.

Helminth parasites of the wood mouse, Apodemus sylvaticus (n = 440), were surveyed in five localities, comprising woodland and grassland sites, in Southern England. Seven species of helminths were identified, among which Heligmosomoides polygyrus and Syphacia stroma were dominant (prevalence = 79.1% and 54.1%, respectively). Less common species were the trematode Corrigia vitta (14.8%), cestodes Catenotaenia pusilla (8.4%), Hydatigera taeniaeformis (4.1%) and Microsomacanthus crenata (3.4%) and the nematode Aonchotheca murissylvatici (0.2%). Differences in prevalences between localities were found for H. polygyrus, H. taeniaeformis and M. crenata and in abundances of H. polygyrus, S. stroma and C. vitta. Age-dependent increases in both parameters were identified among species and for helminth species richness. The only species to show significant host sex bias was S. stroma with prevalence values being higher in male mice. A number of different methods for exploiting raw data, and data corrected for significant confounding factors, were used to determine whether there were significant associations (prevalence) between species or quantitative interactions (abundance). The strongest evidence for a positive association was shown in concurrent infections with the trematode C. vitta and the cestode C. pusilla (significant in the whole dataset and evident in each locality, both sexes and both age classes). The abundance of C. pusilla was also higher in mice with C. vitta and vice versa. Overall, however, there was little support for associations or quantitative interactions between species, especially after data had been corrected for significant extrinsic/intrinsic factors, and we conclude that the helminths of wood mice in these communities are largely non-interactive and hence, perhaps better referred to as assemblages.

Anti-Trichuris mucosal responses are maintained during H. bakeri co-infection despite impaired parasite expulsion.

In endemic regions concurrent infection with multiple gastrointestinal (GI) helminth species is more common than single species infection. However, the majority of model helminth infections focus on single species infections leading to a lack of understanding of how co-infection influences anti-parasite immune responses. Here, we use a model co-infection of Trichuris muris (Tm) and Heligmosomoides bakeri (Hb) to investigate the effect of Hb on anti-Tm immune responses. We observed a complete impairment of Tm expulsion in immune competent C57BL/6 mice when co-infected with Hb. This was coupled with reduced cellularity in the colonic mesenteric lymph node (cMLN) proximal to the caecum, however, cMLN cytokine responses and caecal mucosal immune responses in co-infected mice were not significantly different from mice infected with Tm alone. Interestingly, in immune-compromised mice, we found co-infection resulted in enhanced growth and fecundity of female Tm parasites. These data suggest that during helminth-helminth co-infection, immune-independent signals between species may promote survival and growth.

Assessment of anthelmintic potentials of Myrtus communis against Haemonchus contortus and Heligmosomoides polygyrus.

Anthelmintic resistance in grazing livestock systems has been spreading worldwide in prevalence and severity. Therefore, alternative measures including the use of herbal anthelmintic is considered as one of the successful approaches for the control of anthelmintic resistance. In the present report, we describe the chemical constituents of Myrtus communis essential oil, its in vitro anthelmintic effect against the most pathogenic gastrointestinal parasite of sheep; Haemonchus contortus and its in vivo anthelmintic potential using an in vivo gastrointestinal parasite model of rodents; i.e. Heligmosomoides polygyrus. Chromatographic analyzes of the essential oil (EO) extracted from the leaves of M. communis have shown that this oil was composed mainly of a α-pinene (33.59%), eucalyptol (23.85%) and limonene (14.70%). Regarding the in vitro anthelmintic potential, the ovicidal effect was confirmed in an egg hatch inhibition assay at IC50 = 0.7 mg/mL and with 95.83% of immobility of adult worm's after 8 h of exposure to 2 mg/mL of M. communis EO. The anthelmintic capacity of M. communis EO was also confirmed by in vivo assays conducted against the murine parasite H. polygyrus. In fact, at 1200 mg/kg bw of M. communis EO, a reduction of 99.70% in faecal egg counts was observed after 7 days of oral treatment, together with a 71.12% reduction in total worm counts. Based on the obtained results, M. communis EO showed relevant in vitro and in vivo anthelmintic effects against gastro-intestinal parasites.

Suppressive mechanisms by Heligmosomoides polygyrus-induced Tregs in C57BL/6 mice change over time and differ to that of naïve mice.

Disrupting or harnessing immune suppression is leading to new therapeutic avenues in a number of immune-related diseases. Understanding the suppressive functions of regulatory T cells (Tregs) in different environments is therefore key. Parasitic worms are strong inducers of Tregs and previous research has suggested that parasite-induced Tregs are stronger suppressors than naïve Tregs. In strains susceptible to the intestinal worm Heligmosomoides polygyrus, like C57BL/6 mice, it has been hypothesized that increased Treg suppression downregulates both Th1 and Th2 responses, leading to chronic infections and high worm burden. Here, we show that the suppressive capacity of Tregs is no different between cells from infected and/or naive animals. In vitro suppression induced by CD4+ CD25+ Tregs (Peyers' Patches or the mesenteric lymph nodes), isolated early (day 7, tissue dwelling phase) or late (day 21, luminal phase) during infection was similar to that induced by cells from naïve animals. Suppression was CTLA-4 dependent in Tregs from acute but not chronic infection or in Tregs from naïve animals. This highlights the versatility of Tregs and the importance of extensive Treg characterization prior to potential in vivo manipulation of this cell type.

Supplemented nutrition decreases helminth burden and increases drug efficacy in a natural host-helminth system.

Gastrointestinal (GI) helminths are common parasites of humans, wildlife, and livestock, causing chronic infections. In humans and wildlife, poor nutrition or limited resources can compromise an individual's immune response, predisposing them to higher helminth burdens. This relationship has been tested in laboratory models by investigating infection outcomes following reductions of specific nutrients. However, much less is known about how diet supplementation can impact susceptibility to infection, acquisition of immunity, and drug efficacy in natural host-helminth systems. We experimentally supplemented the diet of wood mice (Apodemus sylvaticus) with high-quality nutrition and measured resistance to the common GI nematode Heligmosomoides polygyrus. To test whether diet can enhance immunity to reinfection, we also administered anthelmintic treatment in both natural and captive populations. Supplemented wood mice were more resistant to H. polygyrus infection, cleared worms more efficiently after treatment, avoided a post-treatment infection rebound, produced stronger general and parasite-specific antibody responses, and maintained better body condition. In addition, when applied in conjunction with anthelmintic treatment, supplemented nutrition significantly reduced H. polygyrus transmission potential. These results show the rapid and extensive benefits of a well-balanced diet and have important implications for both disease control and wildlife health under changing environmental conditions.

Long-term trends in helminth infections of wood mice (Apodemus sylvaticus) from the vicinity of Malham Tarn in North Yorkshire, England.

Helminth infections in wood mice (n = 483), trapped over a period of 26 years in the woods surrounding Malham Tarn in North Yorkshire, were analysed. Although 10 species of helminths were identified, the overall mean species richness was 1.01 species/mouse indicating that the helminth community was relatively depauperate in this wood mouse population. The dominant species was Heligmosomoides polygyrus, the prevalence (64.6%) and abundance (10.4 worms/mouse) of which declined significantly over the study period. Because of the dominance of this species, analyses of higher taxa (combined helminths and combined nematodes) also revealed significantly declining values for prevalence, although not abundance. Helminth species richness (HSR) and Brillouin's index of diversity (BID) did not show covariance with year, neither did those remaining species whose overall prevalence exceeded 5% (Syphacia stroma, Aonchotheca murissylvatici and Plagiorchis muris). Significant age effects were detected for the prevalence and abundance of all higher taxa, H. polygyrus and P. muris, and for HSR and BID, reflecting the accumulation of helminths with increasing host age. Only two cases of sex bias were found; male bias in abundance of P. muris and combined Digenea. We discuss the significance of these results and hypothesize about the underlying causes.

Essential oil of Mentha pulegium induces anthelmintic effects and reduces parasite-associated oxidative stress in rodent model.

Following the previous findings reported by the present authors on the anthelmintic effect of hydro-ethanolic extract of Mentha pulegium, the volatile constituents of M. pulegium are now assessed in the present study by exploring its anthelmintic and its antioxidant proprieties using in vitro and in vivo assays. Egg hatch assay (EHA) and adult worm's motility assays (AWMA) were used to assess the in vitro activity against Haemonchus. contortus. The in vivo anthelmintic potential was evaluated in mice infected with Heligmosomoides polygyrus using faecal egg count reduction (FECR) and total worm count reduction (TWCR). M. pulegium EO demonstrated 100% inhibition in the EHA at 200 µg/mL (IC50 = 56.36 µg/mL). In the AWM assay, EO achieved total worms paralysis 6 h after treatment exposure. This nematicidal effect was associated to morphological damages observed in the cuticular's worm using environmental scanning electron microscopy (ESEM). At 400 mg/kg, M. pulegium oil showed 75.66% of FECR and 80.23% of TWCR. The antioxidant potential of this plant was also monitored by several in vitro assays: total antioxidant capacity was 205.22 mg GAE/g DW, DPPH quenching effect was IC50 = 140 µg/mL, ABTS activity IC50 = 155 µg/mL and FRAP effect of 660 µg/mL. Regarding the in vivo assay, M. pulegium EO demonstrated a protective effect against oxidative stress by increasing the activity of the endogenous antioxidants (SOD, CAT and GPx) during H. polygyrus infection.

The development of spicules in Heligmosomoides bakeri (Nematoda, Heligmosomidae).

The spicules of male parasitic nematodes are key morphological features, which vary between species in shape and length and are used often for species identification. However, little is known about spicules and particularly if/how their length varies during growth. We first assessed the degree of variation in spicule length of male Heligmosomoides bakeri 21 days post infection (PI), and then in two follow-up experiments measured spicule lengths at half daily/daily intervals between days 6 and 14 PI. Mean spicule length in 21-day worms was 0.518 mm with a range of 94 µm, and variation between the two spicules of individual worms from 2 to 32 µm. Spicules were first detectable on day 6-6.5, after which their lengths increased until day 7 PI (mean = 0.61 and 0.59). This was followed by significant contraction, initially relatively quickly over the following 48 h and then more slowly over a longer period, stabilizing by days 10-14, with only minor further reduction in length. We conclude that the length of spicules varies significantly over the first few days after they have formed, and, consequently, the age of worms is an important factor for consideration when spicule lengths are measured for experimental/diagnostic or taxonomical purposes.

The effect of conventional preservatives on spicule length of Heligmosomoides bakeri (Nematoda, Heligmosomidae).

Nematode spicules vary in shape and size even between closely related species and, therefore, constitute key characters in nematode taxonomy for distinguishing between species. Spicules are seldom measured on fresh specimens, but rather at some time after extraction from culled hosts and after a period of preservation of the worms in chemical fixatives or by freezing. We carried out two experiments to assess the effects of freezing in Hanks' balanced salt solution, 70% or 80% ethanol and 10% formalin (both of the latter at room temperature and after storage at -80°C) on spicule length of Heligmosomoides bakeri at two time intervals after extraction from mice (Experiment 1, one and four weeks; Experiment 2, one and four months). In Experiment 1, no significant differences were detected, although there was some variation between treatments and over time. In Experiment 2, spicule length varied significantly between treatments and over time, the greatest shrinkage being in 80% ethanol and the least in 10% formalin. However, overall variation in spicule length was very limited, accounting for no more than 5.03% change in length over time and 4.95% between treatments at any of the periods of assessment. Therefore, while whole nematodes can shrivel and shrink in preservatives, making many measurements unreliable, our data indicated that spicule lengths are very little changed by preservation techniques over time, and so spicule length remains as a reliable taxonomic character.

Spatial interactions between two nematode species along the intestine of the wood mouse Apodemus sylvaticus from woodland and grassland sites in southern England.

The distributions of the nematode parasites Heligmosomoides polygyrus and Syphacia stroma were quantified in three equal-length sections along the intestine of wood mice (Apodemus sylvaticus) trapped in three different locations in the south of England. The distribution of H. polygyrus did not change in the presence of S. stroma, this species being largely confined to the anterior third of the intestine, whether S. stroma was or was not present. However, while in single infections with S. stroma, worms were equally distributed in the anterior and middle sections of the intestine, in the presence of H. polygyrus, a higher percentage of worms was located in the middle section. This was a dose-dependent response by S. stroma to increasing worm burdens with H. polygyrus, and even relatively low intensities of infection with H. polygyrus (e.g. ≤10 worms) were sufficient to cause a posterior redistribution of S. stroma into the middle section. A similar posterior shift in the percentage distribution of S. stroma in the intestine was evident in juvenile and mature mice of both sexes, and in mice from all three study sites. The ecological significance of these results is discussed.

Interactions between macrophages and helminths.

Macrophages, the major population of tissue-resident mononuclear phagocytes, contribute significantly to the immune response during helminth infection. Alternatively activated macrophages (AAM) are induced early in the anti-helminth response following tissue insult and parasite recognition, amplifying the early type 2 immune cascade initiated by epithelial cells and ILC2s, and subsequently driving parasite expulsion. AAM also contribute to functional alterations in tissues infiltrated with helminth larvae, mediating both tissue repair and inflammation. Their activation is amplified and occurs more rapidly following reinfection, where they can play a dual role in trapping tissue migratory larvae and preventing or resolving the associated inflammation and damage. In this review, we will address both the known and emerging roles of tissue macrophages during helminth infection, in addition to considering both outstanding research questions and new therapeutic strategies.

The intestinal milieu influences the immunoproteome of male and female Heligmosomoides polygyrus bakeri L4 stage.

The gastrointestinal nematode Heligmosomoides polygyrus bakeri shows enhanced survival in mice with colitis. As the antibody response plays an important role in antiparasitic immunity, antibodies against male and female L4 H. polygyrus were examined in mice with and without colitis. Levels of specific antibodies in the mucosa and serum were determined by enzyme-linked immunosorbent assay and immunogenic proteins of male and female parasites were identified using 2D electrophoresis and mass spectrometry. The function of identified proteins was explored with Blast2Go. Nematodes in mice with colitis induced higher levels of specific immunoglobulin G (IgG1) and IgA, a lower level of IgE in the small intestine and a higher level of IgE in serum against female L4. Infected mice with colitis recognized 12 proteins in male L4 and 10 in female L4. Most of the recognized proteins from male L4 were intermediate filament proteins, whereas the proteins from female L4 were primarily actins and galectins. Nematodes from mice with colitis were immunogenically different from nematodes from control mice. This phenomenon gives new insights into helminth therapy as well as host-parasite interactions.

Neuronal impairment following chronic Toxoplasma gondii infection is aggravated by intestinal nematode challenge in an IFN-γ-dependent manner.

BACKGROUND: It has become increasingly evident that the immune and nervous systems are closely intertwined, relying on one another during regular homeostatic conditions. Prolonged states of imbalance between neural and immune homeostasis, such as chronic neuroinflammation, are associated with a higher risk for neural damage. Toxoplasma gondii is a highly successful neurotropic parasite causing persistent subclinical neuroinflammation, which is associated with psychiatric and neurodegenerative disorders. Little is known, however, by what means neuroinflammation and the associated neural impairment can be modulated by peripheral inflammatory processes. METHODS: Expression of immune and synapse-associated genes was assessed via quantitative real-time PCR to investigate how T. gondii infection-induced chronic neuroinflammation and associated neuronal alterations can be reshaped by a subsequent acute intestinal nematode co-infection. Immune cell subsets were characterized via flow cytometry in the brain of infected mice. Sulfadiazine and interferon-γ-neutralizing antibody were applied to subdue neuroinflammation. RESULTS: Neuroinflammation induced by T. gondii infection of mice was associated with increased microglia activation, recruitment of immune cells into the brain exhibiting Th1 effector functions, and enhanced production of Th1 and pro-inflammatory molecules (IFN-γ, iNOS, IL-12, TNF, IL-6, and IL-1ß) following co-infection with Heligmosomoides polygyrus. The accelerated cerebral Th1 immune response resulted in enhanced T. gondii removal but exacerbated the inflammation-related decrease of synapse-associated gene expression. Synaptic proteins EAAT2 and GABAAα1, which are involved in the excitation/inhibition balance in the CNS, were affected in particular. These synaptic alterations were partially recovered by reducing neuroinflammation indirectly via antiparasitic treatment and especially by application of IFN-γ-neutralizing antibody. Impaired iNOS expression following IFN-γ neutralization directly affected EAAT2 and GABAAα1 signaling, thus contributing to the microglial regulation of neurons. Besides, reduced CD36, TREM2, and C1qa gene expression points toward inflammation induced synaptic pruning as a fundamental mechanism. CONCLUSION: Our results suggest that neuroimmune responses following chronic T. gondii infection can be modulated by acute enteric nematode co-infection. While consecutive co-infection promotes parasite elimination in the CNS, it also adversely affects gene expression of synaptic proteins, via an IFN-γ-dependent manner.

Intestinal nematode infection exacerbates experimental visceral leishmaniasis.

Leishmania donovani exposure often results in subclinical infection in immunocompetent individuals, and the factors dictating development of visceral leishmaniasis (VL) are not known. Infection with intestinal worms skew immunity towards type 2 and regulatory responses, thereby theoretically increases susceptibility to intracellular infections controlled by type 1 responses. Here we have tested how chronic infection with the intestinal nematode Heligmosomoides polygyrus affected immunity to a secondary infection with L donovani. We found that mice infected with H polygyrus displayed higher Leishmania burden in liver and spleen compared to worm-free animals. This increased infectious load was accompanied by reduced leucocyte infiltration and nos2 transcription in livers and increased il4 and il10 transcription in spleens. Collectively, these data show that chronic infection with intestinal nematodes skew immune responses in a way that may favour development of VL.

Parasitic nematodes simultaneously suppress and benefit from coccidian coinfection in their natural mouse host.

Within-host interactions among coinfecting parasites are common and have important consequences for host health and disease dynamics. However, these within-host interactions have traditionally been studied in laboratory mouse models, which often exclude important variation and use unnatural host-parasite combinations. Conversely, the few wild studies of within-host interactions often lack knowledge of parasite exposure and infection history. Here we exposed laboratory-reared wood mice (Apodemus sylvaticus) that were derived from wild-caught animals to two naturally-occurring parasites (nematode: Heligmosomoides polygyrus, coccidia: Eimeria hungaryensis) to investigate the impact of coinfection on parasite infection dynamics, and to determine if the host immune response mediates this interaction. Coinfection led to delayed worm expulsion and prolonged egg shedding in H. polygyrus infections and lower peak E. hungaryensis oocyst burdens. By comparing antibody levels between wild and colony-housed mice, we also found that wild mice had elevated H. polygyrus-IgG1 titres even if currently uninfected with H. polygyrus. Using this unique wild-laboratory system, we demonstrate, for the first time, clear evidence for a reciprocal interaction between these intestinal parasites, and that there is a great discrepancy between antibody levels measured in the wild vs those measured under controlled laboratory conditions in relation to parasite infection and coinfection.

L4 stage Heligmosomoides polygyrus prevents the maturation of dendritic JAWS II cells.

Helminths and their products are strong candidates for the treatment of autoimmunological disorders and allergies. Being a key population of antigen-presenting cells, dendritic cells play a crucial role in the therapeutic potential of worms. The study compares the effects of live pre-male and pre-female L4 stage Heligmosomoides polygyrus administration on the maturation and activation of the JAWS II line of immature dendritic cells. On stimulation with L4 stage H. polygyrus, JAWS II cells acquire semi-mature status and induce Th2 and regulatory responses in vitro. The strongest immunosuppressive effect on JAWS II cells was observed following stimulation with both sexes of nematodes together; this was manifested as immature dendritic cell morphology, proliferation inhibition, cell cycle change, decreased translocation of NF-κB into the nucleus, and lower expression of surface cellular costimulatory molecules CD80, CD86 and MHC I. However, greater production of proinflammatory (IL-12p70, TNF-α, IL-6) and Th2 response-promoting cytokines (IL-4) was observed by JAWS II following exposure to both sexes compared to male or female larvae alone. Sex had no influence on the viability, apoptosis process or endocytosis abilities of the JAWS II cell line. The findings indicate that the presence of only a single sex of the parasite influences a developed response, resulting in reduced proinflammatory and an antiparasitic reaction.

Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota.

BACKGROUND: Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear. OBJECTIVE: Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model. METHODS: A murine helminth/RSV coinfection model was developed. Mice were infected by means of oral gavage with 200 stage 3 H polygyrus larvae. Ten days later, mice were infected intranasally with either RSV or UV-inactivated RSV. RESULTS: H polygyrus-infected mice showed significantly less disease and pulmonary inflammation after RSV infection associated with reduced viral load. Adaptive immune responses, including TH2 responses, were not essential because protection against RSV was maintained in Rag1-/- and Il4rα-/- mice. Importantly, H polygyrus infection upregulated expression of type I interferons and interferon-stimulated genes in both the duodenum and lung, and its protective effects were lost in both Ifnar1-/- and germ-free mice, revealing essential roles for type I interferon signaling and microbiota in H polygyrus-induced protection against RSV. CONCLUSION: These data demonstrate that a strictly enteric helminth infection can have remote protective antiviral effects in the lung through induction of a microbiota-dependent type I interferon response.